A Fix For Gender-Bias In Animal Research Could Help Humans

There's been a male tilt to biomedical research for a long time.

The National Institutes of Health is trying to change that and is looking to bring gender balance all the way down to the earliest stages of research. As a condition of NIH funding, researchers will now have to include female and male animals in their biomedical studies.

As late as the 1990s, researchers worried that testing drugs in women who could be pregnant or become pregnant might lead to birth defects, so experimental drugs were mainly tested in men. Research in animals followed the same pattern.

"There was not the understanding that it really isn't scientifically appropriate to study men and apply your findings to women. We just didn't know that back then," says Dr. Janine Clayton, director of the Office of Research on Women's Health at the NIH.

When the drugs this way finally went to market and women took them, sometimes things went wrong. To try to fix the problem, the NIH and Congress required that women and men be included in research involving human subjects.

Now, there are more women than men participating in clinical trials, at least in studies funded by the NIH. But there's still a mystery: Why do women still report many more bad reactions to medications than men do?

"Men and women respond to medications differently. In fact, one study looked at the drugs that have been taken off the market and 8 of the 10 drugs taken off the market in that particular time period had more severe effects in women," says Clayton.

She thinks the problems that women experience when they take medications could stem from how biomedical research is conducted at the earliest stages – in animals.

"Eighty percent of drug studies that are done in mice are done in male mice," says Clayton.

Studies in mice are important because the results often inform what will be tested in humans.

It's not as if people are ignoring female animals because they're chauvinists. Some researchers say females have been excluded from studies because their hormone cycles can confound the experiments, though the actual variability that the estrus cycle introduces is debatable.

And in some cases, research has been skewed the other way. Male animals are sometimes excluded from studies because they fight with each other, which can complicate results, and because the males sometimes have to be caged separately, which can drive up costs in cash-strapped labs.

In other cases, studies are done on both male and female animals, but the data on each sex don't get reported separately.

All in all, Clayton says, researchers are missing indicators early on about how different bodies would respond to medications. "We're learning late," she says. "That's not the best way to do this. We need to study both sexes throughout the entire research spectrum."

So, Clayton and her colleagues drew up a policy starting Jan. 25 that applies to NIH-funded biomedical research starting January 25 on out involving animals with spines. "We're asking scientists to think about sex, to study both male and female animals in their preclinical research so that we can learn more about both male and female biology," says Clayton.

When the policy was first announced, people were pumped about it, says Sarah Richardson, a professor at Harvard who studies the history and philosophy of science. "People were like 'Absolutely, that's terrible. Why aren't they studying female mice?' That was my response, too," she says. "It was seen as just a straightforward obvious corrective that we have to do."

But she and other researchers maintain that if the goal is to address women's health inequities, the policy on animal research isn't likely to be effective by itself. Mice aren't people. Richardson also says the focus on animals could distract scientists from the big picture: what happens in real living humans.

"Women on average, in North America at least, take more prescription drugs than men do," she says. "Women also go to the doctor more. We all know this — we cannot get the men in our lives to go to the doctor. They are also for whatever reason more likely to be sensitive to and prone to report feelings of discomfort," she says. "So, what we thought when we reviewed this literature is, OK, if the NIH is really wanting to address this, we need tons more studies of just those kinds of factors," says Richardson.

The NIH put $10 million toward helping labs add sex and gender to their projects. But if they want to figure out health differences between men and women, Richardson says, they need to also put money towards understanding what drives differences in human behavior.

It's not always simple to account for sex and gender in research projects, says Stacey Ritz, an immunologist at McMaster University in Canada who wrote a guide on how to do so. "I've really struggled with it for many years," she says.

She says in most cases it's pretty straightforward to do a male-female comparison. But there's a danger in assuming that a difference noticed between male and female animals stems from a difference in their basic biology, rather than because of something else, like how the male animals might have been housed alone while the female animals were housed in groups.

"That's one of the things that concern me," says Ritz. "A lot of times the questions around social dynamics and gender get glossed over and it's assumed — especially with animals — that differences you see between male and female are purely biologically driven," says Ritz.

Neurologist Rhonda Voskuhl, at UCLA, agrees that mice aren't going to reveal all the intricacies of why human men and women can have different health outcomes. "There's no perfect model for the human except for the human," says Voskuhl.

But in many cases, she says, animal studies can uncover important findings that can make a difference for people.

Voskuhl has seen that firsthand. She directs UCLA's research program on multiple sclerosis. She says for quite a while, researchers didn't report the sex of animals they studied, though many studied mainly male rats. When they started looking more closely at female animals, they realized the disease progressed differently in them.

That knowledge has led to findings about how to treat multiple sclerosis in women, including the idea that a pregnancy hormone could relieve symptoms, an approach that's in clinical trials.

"The point of the story is, you may not think there's anything there until you study it," says Voskuhl.

She says research on animals and humans goes hand in hand. If researchers study and report data for both sexes, that may well dredge up new treatment possibilities in people.

A similar case came up in Jeff Mogil's work studying pain at McGill University in Canada. He says a few decades ago, people primarily studied male animals, which they'd order from a company. The lab he worked in studied both.

"And because of that I've been in a position to see sex differences where other people in my field haven't simply because they never had female mice lying around," says Mogil.

By studying both sexes, Mogil and his colleagues found that different cells communicate pain in female and male animals. "They experienced pain in the exact same way and to exactly the same degree, but the pain is produced and modulated using different circuits," Mogil says.

If the same is true in people, that difference could have big implications for a class of painkillers meant to work by blocking the cells that are more active in men. "The prediction would be those drugs simply won't work at all in women. It's not that they'll work better in women and worse in men. It's that they won't work in women period," he says.

And, he says, if people running clinical trials on that drug didn't know that it only worked in men, they might look at the trial data, see that it only worked in half the participants, and just ditch it entirely.